title: β-amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3.
abstract: Accumulating evidence suggests that glycogen synthase kinase 3 (GSK-3) is a multifunctional kinase implicated in Alzheimer's disease (AD). However, the synaptic actions of GSK-3 in AD conditions are largely unknown. In this study, we examined the impact of GSK-3 on N-methyl-D-aspartate receptor (NMDAR) channels, the major mediator of synaptic plasticity. Application of GSK-3 inhibitors or knockdown of GSK-3 caused a significant reduction of NMDAR-mediated ionic and synaptic current in cortical neurons, whereas this effect of GSK-3 was impaired in cortical neurons treated with β-amyloid (Aβ) or from transgenic mice overexpressing mutant amyloid precursor protein. GSK-3 activity was elevated by Aβ, and GSK-3 inhibitors failed to decrease the surface expression of NMDA receptor NR1 (NR1) and NR1/postsynaptic density-95 (PSD-95) interaction in amyloid precursor protein mice, which was associated with the diminished GSK-3 regulation of Rab5 activity that mediates NMDAR internalization. Consequently, GSK-3 inhibitor lost the capability of protecting neurons against N-methyl-D-aspartate-induced excitotoxicity in Aβ-treated neurons. These results have provided a novel mechanism underlying the involvement of GSK-3 in AD.
authors.affiliation: Department of Neurology and Institute of Neurology, Ruijin Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Deng
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xiong
authors.forename: Paul
authors.initials: P
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Shengdi
authors.initials: S
authors.lastname: Chen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D016202:N-Methylaspartate / Q000633:toxicity; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D007211:Indoles; D008301:Maleimides; D016194:Receptors, N-Methyl-D-Aspartate; C417521:SB 216763; D016202:N-Methylaspartate; D038362:Glycogen Synthase Kinase 3; D020696:rab5 GTP-Binding Proteins
keywords: Alzheimer's disease; GSK-3; NMDA receptor; β-amyloid